Abstract
Accumulating data suggests that the initiation and progression of human breast tumors is fueled by a rare subpopulation of tumor cells, termed breast tumor-initiating cells (BTIC), which resist radiotherapy and chemotherapy. Consequently, therapies that abrogate BTIC activity are needed to achieve durable cures for breast cancer patients. To identify such therapies we used a sensitive assay to complete a high-throughput screen of small molecules, including approved drugs, with BTIC-rich mouse mammary tumor cell populations. We found that inhibitors of the serotonin reuptake transporter (SERT) and serotonin receptors, which include approved drugs used to treat mood disorders, were potent inhibitors of mouse BTIC activity as determined by functional sphere-forming assays and the initiation of tumor formation by transplant of drug-exposed tumor cells into syngeneic mice. Moreover, sertraline (Zoloft), a selective serotonin reuptake inhibitor (SSRI), synergized with docetaxel (Taxotere) to shrink mouse breast tumors in vivo. Hence drugs targeting the serotonergic system might be repurposed to treat breast cancer patients to afford more durable breast cancer remissions.
Highlights
Breast cancer was the first malignancy of solid epithelial tumors reported to follow the cancer stem cell (CSC) model [1]
Tumors following the CSC model comprise a cellular hierarchy of breast tumor-initiating cells (BTIC) at their apex and non-tumorigenic differentiating BTIC progeny at their base
We recently reported that various transgenic mouse models of breast cancer, including those shown to follow the CSC model, comprise a high fraction of BTIC [6], as determined by limiting dilution tumor cell transplantation experiments, the “gold standard” assay for tumor-initiating cells [14]
Summary
Breast cancer was the first malignancy of solid epithelial tumors reported to follow the cancer stem cell (CSC) model [1]. We recently reported that various transgenic mouse models of breast cancer, including those shown to follow the CSC model, comprise a high fraction of BTIC [6], as determined by limiting dilution tumor cell transplantation experiments, the “gold standard” assay for tumor-initiating cells [14]. We showed that tumor cells isolated from mouse mammary tumors maintain a high BTIC frequency [6] when propagated in serum-free, chemically-defined medium first developed to culture mouse neuronal stem and progenitor cells [16]. By contrast, propagating the tumor cells in serum-containing medium reduced BTIC frequencies by 4–5 orders of magnitude [6] We reasoned that these models would enable us to complete highthroughput screens with BTIC-enriched mouse mammary tumor cells and thereby identify agents targeting BTIC, which could be subsequently tested for their capacity to abrogate the tumorigenicity of their human counterparts. 5-HT signalling has previously been implicated in postnatal mammary gland development [18, 19] and linked to breast cancer [20]
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